Method of synthesizing 1alpha-hydroxy-2-methylene-19-nor-homopregnacalciferol

ABSTRACT

A method of making 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol. The method includes the steps of condensing a bicyclic ketone with an allylic phosphine oxide to produce a protected 19-nor-pregnacalciferol analog, thereafter cleaving the protecting group to form 22-alcohol, converting the alcohol to an ester, reducing the ester to 17β-isopropyl-19-nor-vitamin D analog, and finally deprotecting the 17β-isopropyl derivative to form the desired compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/397,135filed Mar. 26, 2003, now U.S. Pat. No. 6,774,251 which is based on andclaims priority from provisional patent Application No. 60/369,159 filedon Mar. 29, 2002.

BACKGROUND OF THE INVENTION

The natural hormone, 1α,25-dihydroxyvitamin D₃ and its analog in theergosterol series, i.e. 1α,25-dihydroxyvitamin D₂ are known to be highlypotent regulators of calcium homeostasis in animals and humans, and morerecently their activity in cellular differentiation has beenestablished, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987).Many structural analogs of these metabolites have been prepared andtested, including 1α-hydroxyvitamin D₃, 1α-hydroxyvitamin D₂, variousside chain homologated vitamins and fluorinated analogs. Some of thesecompounds exhibit an interesting separation of activities in celldifferentiation and calcium regulation. This difference in activity maybe useful in the treatment of a variety of diseases such as renalosteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis,and certain malignancies.

Recently, a new class of vitamin D analogs has been discovered, i.e. theso called 19-nor-vitamin D compounds, which are characterized by thereplacement of the A-ring exocyclic methylene group (carbon 19), typicalof the vitamin D system, by two hydrogen atoms. Biological testing ofsuch 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D₃) revealed aselective activity profile with high potency in inducing cellulardifferentiation, and very low calcium mobilizing activity. Thus, thesecompounds are potentially useful as therapeutic agents for the treatmentof malignancies, or the treatment of various skin disorders. Twodifferent methods of synthesis of such 19-nor-vitamin D analogs havebeen described [Perlman et al., Tetrahedron Lett. 31, 1823 (1990);Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al.,U.S. Pat. No. 5,086,191)].

In U.S. Pat. No. 4,666,634, 2β-hydroxy and alkoxy (e.g., ED-71) analogsof 1α,25-dihydroxyvitamin D₃ have been described and examined by Chugaigroup as potential drugs for osteoporosis and as antitumor agents. Seealso Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989).Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkylgroups) A-ring analogs of 1α,25-dihydroxyvitamin D₃ have also beenprepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111(1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner etal., J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617 (1995).Recently, similar analogs of 1α,25-dihydroxy-19-norvitamin D₃ have alsobeen synthesized, i.e., compounds substituted at 2-position with hydroxyor alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), which exhibitinteresting and selective activity profiles. All these studies indicatethat binding sites in vitamin D receptors can accommodate differentsubstituents at C-2 in the synthesized vitamin D analogs.

Recently analogs which are characterized by the transposition of thering A exocyclic methylene group, present in the normal vitamin Dskeleton, from carbon 10 (C-10) to carbon 2 (C-2), i.e.,2-methylene-19-nor-vitamin D compounds, were synthesized and tested.Molecular mechanics studies indicate that such molecular modificationdoes not change substantially the conformation of the cyclohexanediolring A. However, introduction of the 2-methylene group into19-nor-vitamin. D carbon skeleton changes the character of its (1α- and3β-) A-ring hydroxyls. They are both now in the allylic positions,similarly, as 1α-hydroxy group (crucial for biological activity) in themolecule of the natural hormone, 1α,25-(OH)₂D₃. These analogs haveexhibited similar rate of binding to the receptor as1α,25-dihydroxyvitamin D₃ and were also characterized by high celldifferentiation activity. These compounds were characterized by little,if any intestinal calcium transport activity, as compared to that of1α,25-dihydroxyvitamin D₃, while exhibiting relatively high activity, ascompared to that of 1α,25-dihydroxyvitamin D₃ in their ability tomobilize calcium from bone.

More than ten years ago an interesting 1α-hydroxyvitamin D analog wassynthesized, namely, 1α-hydroxy-20-methyl-pregnacalciferol (alsosometimes referred to as 1α-hydroxy-homopregnacalciferol) which wasessentially devoid of calcemic activity, showed some HL-60 celldifferentiation ability but unexpectedly exhibited comparable binding tothe receptor as 1α,25-dihydroxyvitamin D₃ [Lau, W. F. (1986) Ph.D.Thesis, University of Wisconsin-Madison]. In a continuing effort toexplore the 19-nor class of pharmacologically important vitamin Dcompounds, a 1α-hydroxy-19-nor-vitamin D analog, which is characterizedby the presence of methylene substituent at the carbon 2 (C-2) and17β-isopropyl side chain has now been synthesized and tested.

SUMMARY OF THE INVENTION

The present invention is directed toward a method of making1α-hydroxy-2-methylene-19-nor-homopregnacalcifeol having the structure

comprising the steps of:

condensing a bicyclic ketone having the structure

with an allylic phosphine oxide having the structure

where Y₁, Y₂ and R, which may be the same or different, are each ahydroxy-protecting group, to produce a protected 19-nor-vitamin D analoghaving the structure

thereafter cleaving the protecting group R to form an alcohol having thestructure

converting said alcohol to an ester having the structure

where R₁ is a tosyl group or a mesyl group;

reducing said ester to obtain 17β-isopropyl vitamin D derivative havingthe structure

and deprotecting said 17β-isopropyl vitamin D derivative to form1α-hydroxy-2-methylene-19-nor-homopregnacalciferol.

DISCLOSURE OF THE INVENTION

A class of 1α-hydroxylated vitamin D compounds not known heretofore arethe vitamin D isomers in which the A-ring exocyclic methylene group,typical of all vitamin D system has been transposed to the carbon 2,i.e. 19-nor-vitamin D analogs, having a methylene group at the2-position.

Structurally the novel analogs are characterized by the general formulaI shown below:

where Y₁ and Y₂, which may be the same or different, are each selectedfrom the group consisting of hydrogen and a hydroxy-protecting group, Rmay be selected from the group consisting of hydrogen, hydroxyl andprotected hydroxyl.

The wavy line to the methyl substituent at C-20 indicates that carbon 20may have either the R or S configuration.

The preparation of1α-hydroxy-20-methyl-2-methylene-19-nor-pregnacalciferol compounds (alsoherein referred to as 1α-hydroxy-2-methylene-19-nor-homopregnacalciferolcompounds) having the basic structure I can be accomplished by a commongeneral method, i.e. the condensation of a bicyclic Windaus-Grundmanntype ketone II with the allylic phosphine oxide III:

In the structures II and III, groups Y₁ and Y₂ and R represent groupsdefined above; Y₁ and Y₂ are preferably hydroxy-protecting groups, R iseither hydrogen, hydroxyl or protected hydroxyl, it being alsounderstood that any functionalities in R that might be sensitive, orthat interfere with the condensation reaction, be suitably protected asis well known in the art. The process shown above represents anapplication of the convergent synthesis concept, which has been appliedeffectively for the preparation of vitamin D compounds [e.g. Lythgoe etal., J. Chem. Soc. Perkin Trans. I, 590 (1978); Lythgoe, Chem. Soc. Rev.9, 449 (1983); Toh et al., J. Org. Chem. 48, 1414 (1983); Baggiolini etal., J. Org. Chem. 51, 3098 (1986); Sardina et al., J. Org. Chem. 51,1264 (1986); J. Org. Chem. 51, 1269 (1986); DeLuca et al., U.S. Pat. No.5,086,191; DeLuca et al., U.S. Pat. No. 5,536,713].

Hydrindanones of the general structure II are known, or can be preparedby known methods. Specific important examples of such known bicyclicketones are Grundmann's ketone analogs (a & b) [Mincione et al., Synth.Commun. 19, 723, 1989; Peterson et al., J. Org. Chem. 51, 1948 (1986)].

2-Methylene phosphine oxide III can be prepared according to theprocedure described by Sicinski et al., J. Med. Chem, 41, 4662 (1998),DeLuca et al., U.S. Pat. No. 5,843,928.

For the preparation of the required Grundmann's ketone analog of thegeneral structure II, a new synthetic route has been developed startingfrom the diol 2, easily obtained from the commercial vitamin D₂ asdescribed by Sardina et al., J. Org. Chem. 51, 1264 (1986). The overallprocess for the synthesis of the vitamin D analog 10 is summarized bythe SCHEME 1. Thus the diol 2, obtained by the ozonolysis of vitamin D₂,was protected as mono triethyl silyl ether 3 and the secondary hydroxylat C-8 was oxidized with PDC to get the Grundmann's ketone 4.Wittig-Homer coupling of the conjugate base of the phosphine oxide 5,produced upon deprotonation with phenyllithium, with the protected22-hydroxy Grundmann's ketone afforded the expected protected19-nor-vitamin D analog 6 in a high yield. The triethylsilyl protectinggroup of the compound 6 was cleaved using 8:8:1 mixture of AcOH:THF:H₂Oto give 22-alcohol 7. This was then converted into its tosyl derivative8 on reaction with p-toluenesulfonyl chloride in pyridine, which onreduction with LiAlH₄ gave the 20-methyl analog 9. The final stepinvolved the unmasking of the silyl ethers with tetrabutylammoniumfluoride to yield1α-hydroxy-20-methyl-2-methylene-19-nor-pregnacalciferol, i.e.1α-hydroxy-2-methylene-19-nor-homopregnacalciferol, 10. An alternativeprocedure for the synthesis of vitamin analog 10 involves theWittig-Homer coupling of the Grundmann's ketone analog b with the2-methylene phosphine oxide 5, followed by the deprotection of silylethers.

EXAMPLE 1

Preparation of 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol(Sometimes also Referred to as1α-hydroxy-20-methyl-2-methylene-19-nor-pregnacalcifeol) 10

a) Ozonolysis of Vitamin D₂

A solution of vitamin D₂ (2.00 g. 5.05 mmol) in absolute methanol (175mL) and pyridine (1.75 mL) was placed in an ozonation vessel providedwith a magnetic stirring bar. The solution was cooled to −78° C. whilepurging with oxygen. Then a stream of ozone was passed until a deep bluecolor appeared (1 h). The ozone flow was discontinued, and the reactionmixture was purged with oxygen (−78° C.) until no ozone remained insolution. Then NaBH₄ (500 mg) was added in one portion, and theresulting solution was stirred at −78° C. for 20 min while a gentle flowof N₂ was maintained. The reaction was allowed to stir at roomtemperature overnight. An additional quantity of NaBH₄ (500 mg) wasadded at room temperature, and the resulting solution was stirred for 30min. The resulting solution was rotary evaporated to a small volume, andthe residue was extracted with ether. The ethereal layers were washedwith 5% HCl and H₂O and then dried over Na₂SO₄. Filtration andconcentration in vacuo afforded a residue that was flash chromatographed(75:25 mixture of hexane/ethyl acetate) to yield diol 2 (1.2 g, 82%): ¹HNMR (CDCl₃) δ0.958 (3H, s, 18-CH₃), 1.03 (2H, d, J=6.6 Hz, 21-CH₃), 3.38(1H, dd, J=10.5, 6.7 Hz, 22-H), 3.64 (1H, dd, J=10.5, 3.5 Hz, 22-H),4.09 (1H, m, 8α-H).

b) Preparation of Silyl Ether 3

De-A,B-23,24-dinor-22-[(triethylsilyl)oxy]-cholan-8β-ol (3). To asolution of the diol 2 (100 mg, 0.472 mmol) in anhydrous acetonitrile(250 μL) and 2,6-lutidine (138 μL, 1.17 mmol) was added triethylsilyltrifluoromethanesulfonate (118 μL, 0.518 mmol). The reaction was thenstirred at room temperature under argon for 2 h, then quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine solution, dried (Na₂SO₄). The organic extracts wereevaporated to get the crude product, which was purified by silica gelchromatography to yield the silyl ether 3 (120 mg, 80%): ¹H NMR (CDCl₃)δ 0.575 (6H, q, 3×SiCH₂), 0.947 (9H, t, 3×SiCH₂CH₃), 0.958 (3H, s,18-CH₃), 1.03 (2H, d, J=6.6 Hz, 21-CH₃), 3.24 (1H, dd, J=9.6, 7.7 Hz,22-H), 3.59 (1H, dd, J=3.5, 9.6 Hz, 22-H), 4.08 (1H, m, 8α-H).

c) Oxidation of the 8β-hydroxyl Group in Compound 3

De-A,B-23,24-dinor-22-[(triethylsilyl)oxy]-8-oxocholane (4). Pyridiniumdichromate (87.6 mg, 0.232 mmol) was added to a solution of alcohol 3(50 mg, 0.155 mmol) and pyridinium p-toluenesulfonate (10 mg) in CH₂Cl₂(2 mL). The resulting orange suspension was stirred for 3 h at roomtemperature. Ether was added, and the resulting suspension was filteredthrough a short column of Celite. The filtrate was washed with asaturated aqueous solution of CuSO₄, and H₂O, dried (Na₂SO₄), andfiltered. Removal of solvents under reduced pressure afforded theketone, which was then purified by column chromatography. The compoundwas further purified by HPLC (250×10 mm Zorbax-Sil column, 4 mL/min)using 90:10 mixture of hexane/ethyl acetate as eluent. Pure protectedketone 4 (38 mg, 79%) was eluted at R_(V) 17 mL: ¹H NMR (CDCl₃) δ 0.582(6H, q, 3×SiCH₂), 0.643 (3H, s, 18-CH₃), 0.952 (9H, t, 3×SiCH₂CH₃),1.036 (3H, d, J=6.1 Hz, 21-CH₃), 3.29 (1H, dd, J=6.9, 9.6 Hz, one of22-H), 3.58 (1H, dd, J=2.8, 9.6 Hz, one of 22-H).

d) Wittig-Homer Condensation of Phosphine Oxide 5 with ProtectedGrundmann's Ketone 4

1α-[(tert-Butyldimethylsilyl)oxy]-(20S)-20-[(triethylsilyl)oxy]methyl-2-methylene-19-nor-pregnacalciferoltert-butyldimethylsilyl ether (6). To a solution of phosphine oxide 5(13 mg, 0.0218 mmol) in anhydrous THF (130 μL) at 0° C. was slowly addedPhLi (18 μL, 0.0327 mmol) under argon with stirring. The solution turneddeep orange. The mixture was cooled to −78° C. and a precooled (−78° C.)solution of protected hydroxy ketone 4 (8.5 mg, 0.0262 mmol) inanhydrous THF (170 μL) was slowly added. The mixture was stirred at −78°C. for 2 h 30 min and then at 0° C. for 18 h. Ethyl acetate was addedand the organic phase was washed with brine, dried (MgSO₄) andevaporated. The residue was dissolved in hexane, applied on a silicaSep-Pak cartridge, and washed with hexane/ethyl acetate (99.7:0.3, 20mL) to give 19-nor-vitamin D derivative 6. The vitamin derivative wasfurther purified by HPLC (250×10 mm Zorbax-Sil column, 4 mL/min) usinghexane/ethyl acetate (99.9:0.1) solvent system. Pure compound 6 waseluted at R_(V) 22 mL as a colorless oil: UV (in ethanol) λ_(max) 244,252, 262 nm; ¹H NMR (CDCl₃) δ 0.026, 0.047, 0.065 and 0.079 (each 3H,each s, 4×SiCH₃), 0.559 (3H, s, 18-CH₃), 0.593 (6H, q, 3×SiCH₂), 0864and 0.894 (each 9H, each s, 2×Si-t-Bu), 0.966 (9H, t, 3×SiCH₂CH₃), 1.019(3H, d, J=6.5 Hz, 21-CH₃), 3.25 (1H, dd, J=9.5, 7.9 Hz, 22-H), 3.62 (1H,dd, J=3.4, 9.6 Hz, 22-H), 4.42 (2H, m, 1α-H, 3β-H), 4.92 and 4.96 (each1H, each s, ═CH₂), 5.84 (1H, d, J=11.2 Hz, 7-H) and 6.21 (1H, d, J=11.2Hz, 6-H); MS m/z (relative intensity): 688 (M⁺, 34), 659 (M⁺-CH₃), 557(M⁺-OSi(CH₃)₂t-Bu, 50).

e) Cleavage of Triethylsilyl Ether in the Vitamin Analog 6

1α-[(tert-Butyldimethylsilyl)oxy]-(20S)-20-hydroxymethyl-2-methylene-19-nor-pregnacalciferoltert-butyldimethylsilyl ether (7). To a solution of the 19-nor-vitamin Dderivative 6 (1.5 mg, 0.002 mmol) in 50 μL benzene was added 200 μL of8:8:1 mixture of AcOH:THF:H₂O and stirred for 2 h. The reaction mixturewas then quenched with aqueous solution of NaHCO₃ and extracted withether. The combined ether layers were washed with brine, dried (Na₂SO₄)and the solvent evaporated to get the alcohol which was further purifiedby silica column chromatography with 95:5 mixture of hexane/ethylacetate to yield pure 7 (1 mg, 80%): ¹H NMR (CDCl₃) 0.026, 0.047, 0.064and 0.078 (each 3H, each s, 4×SiCH₃), 0.571 (3H, s, 18-CH₃), 0.864 and0.895 (each 9H, each s, 2×Sit-Bu), 1.065 (3H, d, J=6.6 Hz, 21-CH₃), 3.40(1H, dd, J=10.4, 7.0 Hz, 22-H), 3.65 (1H, dd, J=3.3, 15.4 Hz, 22-H),4.42 (2H, m, 1α-H, 3β-H), 4.92 and 4.97 (each 1H, each s, ═CH₂), 5.84(1H, d, J=11.3 Hz, 7-H) and 6.21 (1H, d, J=11.3 Hz, 6-H); MS m/z(relative intensity) 574 (M⁺, 17), 559 (M⁺-CH₃, <1), 442(M⁺-OSi(CH₃)₂t-Bu, 64).

f) Conversion of the Hydroxy Compound 7 into the Tosyl Derivative 8

1α-[(tert-Butyldimethylsilyl)oxy]-(20S)-20-[(p-toluenesulfonyl)oxy]methyl-2-methylene-19-nor-pregnacalciferoltert-butyldimethylsilyl ether (8). A solution of the alcohol 7 (1 mg,0.0017 mmol) and p-toluenesulfonyl chloride (498 μg, 0.0026 mmol) inpyridine (34 μL, 0.0043 mmol) was kept at 0° C. for 3 h. Addition of iceresulted in a suspension that was extracted with ethyl acetate/hexane.The organic extracts were washed with 5% aqueous HCl, H₂O, and saturatedaqueous NaHCO₃, and dried over Na₂SO₄. Removal of the solvents in vacuoafforded a residue that was crystallized from hexane to yield thetosylated product 8 (1 mg, 79%).

g) Reduction of Tosyl Ester 8

1α-[(tert-Butyldimethylsilyl)oxy]-20-methyl-2-methylene-19-nor-pregnacalciferoltert-butyldimethylsilyl ether (9). To the compound 8 (1 mg, 0.0013 mmol)in anhydrous ether (2 mL) was added lithium aluminum hydride (15 μg,0.0038 mmol). The reaction mixture was refluxed for 2 h, cooled andexcess reagent was decomposed by saturated aqueous sodium chloride. Themixture was filtered and layers separated. The aqueous fraction wasextracted with ether. Ether fractions were washed with water, saturatedaqueous sodium chloride, dried (Na₂SO₄), evaporated to dryness and driedunder vacuum to get the crude 17β-isopropyl vitamin D derivative 9. Thecompound was purified on a silica Sep-Pak cartridge using 97:3 mixtureof hexane/ethyl acetate.

9: ¹H NMR (CDCl₃) δ 0.025, 0.047, 0.065 and 0.078 (each 3H, each s,4×SiCH₃), 0.540 (3H, s, 18-CH₃), 0.864 and 0.895 (each 9H, each s,2×Sit-Bu), 0.865 (3H, d, J=6.6 Hz, 22-CH₃), 0.946 (3H, d, J=6.5 Hz,21-CH₃), 4.42 (2H, m, 1α-H, 3βH), 4.92 and 4.97 (each 1H, each s, ═CH₂),5.84 (1H, d, J=11.0 Hz, 7-H) and 6.22 (1H, d, J=11.0 Hz, 6-H).

h) Deprotection of TBDMS Ethers of the Vitamin Analog 9

1α-Hydroxy-20-methyl-2-methylene-19-nor-pregnacalciferol (10). Protectedvitamin 9 (750 μg, 0.0013 mmol) was dissolved in anhydrous THF (150 μL),then tetrabutylammonium fluoride (1 M solution in THF, 4 μL, 0.004 mmol)was added and the mixture was stirred at room temperature for 2 h underargon. The reaction was then quenched with water and extracted withether, washed with brine, dried (Na₂SO₄), and evaporated. The residuewas purified by HPLC (250×6.2 mm Zorbax-ODS reversed phase column, 2mL/min) using methanol/water (95:5) solvent system. Pure vitaminderivative 10 was eluted at R_(V) 9.4 mL (375 μg, 85%): UV (in ethanol)λ_(max) 243.5, 251.5, 262.0 nm; ¹H NMR (CDCl₃) δ 0.547 (3H, s, 18-CH₃),0.865 (3H, d, J=6.6 Hz, 22-CH₃), 0.944 (3H, d, J=6.5 Hz, 21-CH₃), 4.48(2H, m, 1α-H, 3β-H), 5.09 and 5.10 (each 1H, each s, ═CH₂), 5.88 (1H, d,J=11.4 Hz, 7-H) and 6.36 (1H, d, J=11.4 Hz, 6-H); MS m/z (relativeintensity) 330 (M⁺, 100), 312 (M⁺-H₂O), 287 (M⁺-C₃H₇, 22).

As used in the description and in the claims, the term“hydroxy-protecting group” signifies any group commonly used for thetemporary protection of hydroxy functions, such as for example,alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafterreferred to simply as “silyl” groups), and alkoxyalkyl groups.Alkoxycarbonyl protecting groups are alkyl-O—CO-groupings such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies analkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or acarboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl,succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, ora halo, nitro or alkyl substituted benzoyl group. The word “alkyl” asused in the description or the claims, denotes a straight-chain orbranched alkyl radical of 1 to 10 carbons, in all its isomeric forms.Alkoxyalkyl protecting groups are groupings such as methoxymethyl,ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl andtetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl,diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl andanalogous alkylated silyl radicals. The term “aryl” specifies a phenyl-,or an alkyl-, nitro- or halo-substituted phenyl group.

A “protected hydroxy” group is a hydroxy group derivatised or protectedby any of the above groups commonly used for the temporary or permanentprotection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl oralkoxycarbonyl groups, as previously defined. The terms “hydroxyalkyl”,“deuteroalkyl” and “fluoroalkyl” refer to an alkyl radical substitutedby one or more hydroxy, deuterium or fluoro groups respectively.

1. A compound having the structure:

where (a) Y₁ and Y₂, which may be the same or different, are eachselected from the group consisting of hydrogen and a hydroxy-protectinggroup, and R is selected from the group consisting of hydroxyl andprotected hydroxyl; or (b) Y₁ and R are both hydrogen and Y₂ is ahydroxy-protecting group; or (c) Y₂ and R are both hydrogen and Y₁ is ahydroxy-protecting group.
 2. The compound of claim 1 wherein Y₁ and Y₂are both a t-butyl-dimethylsilyl group.
 3. A compound having thestructure:

where Y₁ and Y₂, which may be the same or different, are each selectedfrom the group consisting of hydrogen and a hydroxy-protecting group. 4.The compound of claim 3 wherein Y₁ and Y₂ are both at-butyl-dimethylsilyl group.
 5. A compound having the structure:

where Y₁ and Y₂, which may be the same or different, are each selectedfrom the group consisting of hydrogen and a hydroxy-protecting group,and R₁ is a hydroxy-protecting group.
 6. The compound of claim 5 whereinR₁ is a tosyl group or a mesyl group.
 7. The compound of claim 5 whereinR₁ is a triethylsilyl group.
 8. The compound of claim 5 wherein Y₁ andY₂ are both a t-buyl-dimethylsilyl group.
 9. The compound of claim 8wherein R₁ is a tosyl group.
 10. The compound of claim 8 wherein R₁ is atriethylsilyl group.
 11. A compound having the structure:

where Y₁ and Y₂, which may be the same or different, are each ahydroxy-protecting group.
 12. The compound of claim 11 wherein Y₁ and Y₂are both a t-butyl-dimethylsilyl group.